Total Solid-Phase Synthesis of Dehydroxy Fengycin Derivatives

Abstract

A rapid and efficient solid-phase strategy for the synthesis of dehydroxy fengycins derivatives is described. This synthetic approach involved the linkage of a Tyr to a Wang resin via a Mitsunobu reaction and the elongation of the peptide sequence followed by subsequent acylation of the N-terminus of the resulting linear peptidyl resin, esterification of the phenol group of a Tyr with an Ile, and final macrolactamization. The amino acid composition as well as the presence of the N-terminal acyl group significantly influenced the stability of the macrolactone. Cyclic lipodepsipeptides with a L-Tyr 3 /D-Tyr 9 configuration were more stable than those containing the Tyr residues with an opposite configuration. This work constitutes the first approach on the total solid-phase synthesis of dehydroxy fengycin derivatives.

Fengycin A Analogues with Enhanced Chemical Stability and Antifungal Properties

“…Similar or improved results were obtained when this methodology was employed to prepare 17B – 17D , where we replaced the initial d -Thr residue at position 4 by the fengycin A naturally occurring d -allo-Thr and also their corresponding enantiomers (Figure C). Previous reports have shown that the chirality of the residues within the cyclic core of natural fengycin affects the ease of ring formation. , However, our results in the synthesis of analogues 17B and 17D , using l -amino acids, show that this is not the case for fengycin lactam derivatives, as all of them could be synthesized with similar overall efficacy (50–70% crude purities, Figure C and Figures S23–29). Overall, the synthesis of 17A – D clearly demonstrates the suitability of our synthetic approach for the convenient SPPS of fengycin cyclic lipopeptide amide analogues.…”

“… 24 , 25 This is clearly highlighted by the fact that to date no synthetic strategy has succeeded in delivering a completely natural fengycin peptide and, only very recently, a solid phase peptide synthesis (SPPS) approach which enabled the synthesis of several fengycin analogues was reported. 26 While this marked a significant advance for the field, the reported approach only afforded modest product yields and it did not address the issue of the fengycin peptides’ innate instability.…”

“…Previous reports have shown that the chirality of the residues within the cyclic core of natural fengycin affects the ease of ring formation. 22,26 However, our results in the synthesis of analogues 17B and 17D, using Lamino acids, show that this is not the case for fengycin lactam derivatives, as all of them could be synthesized with similar With peptides 17A−D prepared, we moved to investigate the differences in their chemical stability in comparison to that of the natural product. To this end, biosynthetic fengycin expressed from Bacillus spp.…”

“…Contrary to iturins and surfactins, fengycins display a hydrolytically susceptible aromatic depsi bond between Tyr 3 and Ile 10 , which significantly compromises the structural integrity of its cyclic core (Figure A). , This intrinsic lack of chemical stability means that fengycins are technically challenging to prepare via chemical synthesis. , This is clearly highlighted by the fact that to date no synthetic strategy has succeeded in delivering a completely natural fengycin peptide and, only very recently, a solid phase peptide synthesis (SPPS) approach which enabled the synthesis of several fengycin analogues was reported . While this marked a significant advance for the field, the reported approach only afforded modest product yields and it did not address the issue of the fengycin peptides’ innate instability.…”

Solid-Phase Synthesis of Head to Side-Chain Tyr-Cyclodepsipeptides Through a Cyclative Cleavage From Fmoc-MeDbz/MeNbz-resins

“…Their syntheses are a challenge due to the inherent lability of the phenyl ester bond, which should be formed during the last steps of the synthetic strategy. Feliu and Planas' group developed an elegant strategy (Rosés et al, 2016;Roses et al, 2018), based on the following: incorporation of the first amino acid through the side-chain with the carboxylic acid protected in the form of the allyl ester; elongation of the peptide chain; formation of the phenyl ester with an N-Alloc-amino acid; treatment with Pd(0) to remove the allyl and the Alloc protecting groups; onresin cyclization; and global deprotection and cleavage from the resin.…”